The present invention relates to new rigid chelating structures, methods for preparing the structures and their use in preparing radioimmunoconjugates for SPECT and PET imaging and for radiotherapy.
The use of radiometals to label proteins and antibodies provides a variety of choices of half-life and types of emission(s) for various medical applications in both diagnosis and therapy. Radiometals also offer significant advantages over iodine when used to label monoclonal antibodies. Radiometal labeling, for example, avoids the deleterious effects of oxidation experienced in direct iodination reactions. Labeling with metals can also overcome problems of in vivo deiodination by tumor and normal tissues, particularly when using rapidly internalized antibodies.
Radiometals can generally be attached to antibodies by the use of a "bifunctional chelate" which is first covalently attached to the antibody to form an antibody-chelate conjugate and then bound to the radiometal. The early work in this field used diethylenetriaminepentaacetic acid (DTPA) and its derivatives. This compound has a backbone consisting of three nitrogens separated by two ethylene bridges. The two terminal amine groups each contain two carboxymethyl groups while the internal amine contains one carboxymethyl group. DTPA is generally conjugated to antibodies via its bicyclic anhydride (DTPADA) which forms a covalent amide bond between an antibody amine and one of the carboxylic acid groups of DTPA [Hnatowich, et al. Science 220, 613 (1983)]. This method while convenient has drawbacks. For example, with indium-ill this procedure yields high liver retention and slow body clearance [Goodwin, J. Nucl. Med. 28, 1358 (1987)], as well as a substantial amount of crosslinked antibody (two antibodies linked together by a DTPA bridge). This crosslinking can reduce the immunoreactivity of the antibody, increase liver retention, and decrease tumor uptake.
One strategy available to overcome the problems caused by liver retention is to use chelates which bind the metal strongly thus forming more stable radiometal complexes. Strong metal-ligand bindings are important because weakly bound metals cause increased radiation dose to normal tissues such as kidneys, bone marrow and liver.
Accordingly, there is still a need in the art of radiolabeling for bifunctional ligands which can bind radiometals very strongly thus avoiding increased radiation dose to normal tissues.
It is, therefore, an object of the present invention to provide a new family of functional chelating agents which can bind radiometals very strongly and are capable of surviving in vivo. Another object of the present invention is to provide rigid bifunctional chelating agents which can be conjugated to monoclonal antibodies and other bioactive molecules and overcome the stability problems associated with other prior art chelating agents.